This application focuses on developing novel forms and properties of epsilon-peptides for designing membrane-active peptide chimeras, dimeric ligands of epidermal growth factor receptor (EGFR) and membrane-permeable peptides to characterize the cytoplasmic signaling proteins of tail anchored EGFR ligands. Our results in the current grant period show feasibility of these efforts. In the next grant period, we propose to explore three architectural forms of epsilon-peptides. First, we exploit the soft characters of epsilon-peptide as scaffolds to "fold" four parallel alpha-peptide chains into tetrameric beta-sheet-or sandwich-like epsilon-dendrons that are amphipathic and can function as membrane active peptides. We postulate that the "soft" epsilon-peptide scaffold could form three novel reverse-Lys turns. Together with the appropriately selected beta-strand-forming beta-peptides, they could fold into beta- structures. Our preliminary results show that dendrons with BHHB motifs are amphipathic, membrane permeable and exhibit broad-spectrum antimicrobial activity as well as selective inhibitory activities against proliferation of oncogenically transformed cells. Second, we test oligomeric epsilon-peptides as beta-strand mimetics in single-chain peptides that contain 2beta- or 3beta-strands. We have obtained promising result validating this approach in designing e-peptide mimetics of the 2beta-strand protegrin-1. Third, we exploit the extended polymeric epsilon-peptides as an amphipathic linker to design dimeric EGFR ligands and its antagonist to increase their potency and stability. Since EGFR activation requires binding of two ligands, we propose to use the epsilon-peptide as a linker with definable length for attaching two EGFR ligands by chemo selective ligation developed in the current grant period. This design is guided by the recent x-ray structure of the 2:2 TGFalpha-EGFR complex that shows TGFalpha is separated by 71 angstrom. Finally, we apply the membrane permeable epsilon-peptides with functional cargoes to dissect signaling events mediated by the cytoplasmic tail of EGFR ligands. Because growth factors and their signaling mechanisms are recurring themes in disease pathogenesis, our long-term goal is to develop novel scaffolds and approaches for the design and synthesis of agonists and antagonists relevant to human diseases.